Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment

Igor Branchi

igor
  • Líder del Grupo en el Centro de Ciencias del Comportamiento y Salud Mental, Instituto Italiano de Salud, Roma, Italia.

  • Enfoque especial en las interacciones entre plasticidad neuronas, medicamentos, ambiente y conducta.

Artículos principales

The double-edged sword of neural plasticity

Branchi (2011a) y Branchi (2022)

  • Los niveles altos de plasticidad inducidos por medicamentos, como los antidepresivos serotoninérgicos y los psicodélicos, no son beneficiosos por sí mismos.
  • Una alta plasticidad hace que el cerebro y el comportamiento sean más susceptibles a cambios según factores contextuales, como las condiciones de vida.

A mathematical formula of plasticity: Measuring susceptibility to change in mental health and data science

Branchi (2023) y Delli Colli et al. (2024)

  • Propuesta de fórmula matemática para evaluar la plasticidad, entendida como la susceptibilidad al cambio.
  • Permite identificar, desde un inicio, qué individuos o poblaciones son más propensos a modificar sus resultados conductuales según las terapias o factores contextuales.

Uncovering the determinants of brain functioning, behavior and their interplay in the light of context

Branchi (2024a) y Branchi (2024b)

  • Los sustratos, desde los genes hasta las áreas cerebrales, no tienen un vínculo causal directo con las respuestas conductuales complejas.
  • Mientras el contexto impulsa el comportamiento, los sustratos biológicos limitan el repertorio conductual que se puede implementar.

Otros artículos interesantes de su laboratorio

  • Biomarkers of stress resilience: A review (Paribello et al. 2024)

  • An evolutionary perspective for contemporary psychiatric research Enrico Alleva and Igor Branchi (2011)

  • Epigenetic modifications induced by early enrichment are associated with changes in timing of induction of BDNF expression Branchi et al. (2011)

Introducción

Alboni et al. (2017)

SSRI - Inhibidor selectivo de la recaptación de serotonina

  • Fármacos más prescritos para trastornos de depresión y ansiedad.
  • Mecanismo de acción inmediato: incrementan la concentración de serotonina.
  • Mecanismo de acción antidepresiva parece involucrar mecanismos de plasticidad

Problemáticas

  • 60-70% de los pacientes no experimentan remisión clínica (continúan experimentando síntomas depresivos después de semanas de tratamiento).

    • Evaluada con escalas de severidad (ej Hamilton Rating Scale for Depression) (Zimmerman et al. 2006)
    • Estudio más grande sobre antidepresivos (STAR*D) utilizó un protocolo de HRSD que DUPLICÓ los estimados de remisión de los pacientes (Pigott et al. 2023)
  • 30-40% no muestran respuesta a los medicamentos.

  • Algunos autores han comparado su eficacia con placebos. (Kirsch 2019)

Poco entendimiento de su mecanismo de acción

  • El grupo de Albani propone que hay un poco entendimiento de las vías involucradas en su mecanismo:
    • conductuales, neurogénesis, BDNF, HPA, LTP

Hipótesis de suceptibilidad unidireccional al cambio

  • Antidepresivos no cambian el estado de ánimo por sí mismos

    • Crean una ventana de oportunidad para el cambio

    • Esta a su vez puede ser influenciada por el ambiente, positivo o negativo

    • Ver más en revisión de Branchi (2011b)

    • Psicoplastógenos (Ketamina, LSD, Psilocibina, Iboga, DMT…) tendrían el mismo mecanismo antidepresivo (Carhart-Harris et al. 2018).

Objetivos

  • Estudiar la Hipótesis de suceptibilidad unidireccional al cambio evaluando vías moleculares y celulares afectadas por la administración de SSRI, como expresión de BDNF, neurogénesis, LTP y conducta.

  • Enfoque en el hipocampo por su importancia en procesos de plasticidad y depresión.

Diseño experimental

Animales

Ratones C57BL/6 (12-15 semanas) expuestos a 14 días de estrés (fenotipo de tipo depresivo) seguido de 21 días de 1) ambiente enriquecido, o 2) ambiente estresante.

Conducta

  • Anhedonia

    • Liking-type anhedonia - Saccharin (0.1%)

    • Wanting-type anhedonia - Progressive Ratio: the drive for obtaining a reward

      • Incremento multiplicativo incrementa el número necesario para obtener el reforzador (saccharin)
  • Cognitive Bias

    • discriminar entre 2 luces (azul y amarillo)
    • Una de estas luces presenta una recompenza, la otra un castigo (aire)
    • Después de que aprenden a discriminar, se presenta un estímulo ambiguo
    • Explorar el estímulo ambiguo se considera un bias “optimista”, mientras que no explorarlo es un bias “pesimista”

Fluoxetina en agua (30 mg/kg), 3 semanas

Inmunos

  • ki67 (proliferación, proteína nuclear expresada en todas las fases del ciclo celular menos G0)

  • DCX (neuroblastos en migración y neuronas jóvenes)

    • No es considerado un marcador de neurogénesis per se (combinar con otros marcadores, como BrdU), ver Ohira et al. (2019)
  • Problemáticas de ki67 y DCX en humanos (poblaciones neuronales “dormantes” se han detectado con estos marcadores en nichos no neurogénicos (corteza, amígdala) (Ghibaudi et al. 2023).

RT-PCR (transcriptasa reversa)

  • RNA -> DNA

  • RNA total del hipocampo

Western blot

  • Detectar proteínas en hipocampo y corteza prefrontal.

Electro

  • Electrodo en stratum radiatum (contiene las sinapsis en CA1 que son potenciadas y estudiadas en modelos de LTP por estimulación de CA3 - colaterales de Schaffer)

  • registros orthodromically-evoked fEPSPs

    • Orthodromic: dirección de la propagación. Impulso que viaja en la dirección “natural” (soma - axón - terminal).
    • Evocado: respuesta es inducida.
    • fEPSPs (field Excitatory Postsynaptic Potentials): potenciales registrados en el espacio extracelular (campo) cerca de las neuronas. representan la suma excitatoria de inputs recibidos por un grupo de neuronas, manifestandose como cambios en el voltaje.

Resultados

Efectos contrarios de FLX sobre conductas de tipo depresivas en condiciones enriquecidas y estresantes

Figura 1

  • En condiciones estrsantes, FLX parece empeorar fenotipo depresivo en comparación de vehículo.

  • Sucrose instead of saccharin to assess anhedonia.

  • SSRIs affect metabolism leading to an increased caloric intake and thus to an increased preference for sucrose that is independent from the anhedonic state

FLX en estrés reduce proliferación y reduce volumen de CA1

Figura 2

  • FLX redujo volumen de CA1 en condición estrés comparado con control.

  • Actividad antidepresiva de FLX puede ser independiente de NG

  • Parece que en condiciones estresantes, FLX es detrimental para la proliferación.

Efectos de FLX en vias antidepresivas depende de la calidad del ambiente

Fig 3

  • FLX potencia estas vías en general en condición enriquecida, mientras que parece que pasa lo opuesto en condición estresante

  • FLX modifies molecular and cellular correlates of synaptic plasticity in an environment-dependent manner.

Interacción entre calidad de ambiente y FLX influye sobre receptores y LTP

Fig 4

  • FLX treatment induced an overall increase in the absolute size of field excitatorypostsynaptic potential. FLX-mediated enhancement of the synaptic strength.

  • Overall, these results demonstrate that also the effects of FLX on short- and longterm plasticity in the CA1 region are dependent on the quality of the environment

FLX en condiciones estándar

Fig S5a in the standard condition, FLX did not increase BDNF levels, suggesting that enrichment drives the FLX effects more powerfully than the improvement associated to the standard condition following chronic stress (Supplementary Figure S5)

Discusión

Tabla 1

Shifts from an “uncertain situation (that is, the stress) to a neutral one (that is, the standard condition) leads to an increase in the ability of the organism to cope and control the environment and can thus have beneficial effects

Neurogénesis

Antidepresivos y neurogénesis

carli,2021 ##

  • 5-HT1A y 5-HT4 incrementan BDNF. Bloquear estos receptores reduce efectos neurogénicos de fluoxetina Ménsez-David, 2013

  • Neuronas de GD neurons expresan diferentes receptores de 5-HT (5-HT1A, 5-HT4, 5-HT2A, 5-HT2C y 5-HT7)

  • Incremento de 5-HT por SSRI activa 5HT1A en neuronas maduras de la GCs, (Gi que silencían actividad neuronal (GIRKs) e inhiben función del GD, similar a función de neuronas jóvenes.

  • SSRI producen más efectos plasticos: sinaptogénesis en PFC y amígdala, remodelamiento de espinas dentríticas en hipocampo http://dx.doi.org/10.1016/j.brainresbull.2018.09.002]

LTP

  • stressful condition, FLX significantly enhances plasticity in the CA1 region in comparison with VEH

  • enriched condition, both groups exhibited a robust LTP amplitude, in line with the literature reporting increased LTP levels following enrichment

NMDA

  • increase in neural plasticity induced by FLX administration. Such modifications in neuronal functionality may represent the mechanisms underlying the effects of the drug treatment.

  • ketamine, NMDAR antagonist , produces rapid antidepressant actions (Chen et al. 2022)

    • It is postulated that this increased release of glutamate in the mPFC stimulates prefrontal output to brainstem monoaminergic nuclei, thereby increasing monoaminergic cell firing and prefrontal monoamine efflux (Jiménez-Sánchez et al. 2014)

Demaduración

higihara,2019

Más en (Kobayashi et al. 2010; Ohira et al. 2019)

Relevancia

  • Antidepressants are more effective in patients having a better quality of life

    • socioeconomic status and lifestyle
  • more often to an unfavorable outcome in people living in worst conditions

    • poor-income census tract were significantly more likely to report suicidal ideation than those in the middle- and high- income census tracts (Cohen et al. 2006, 2008)

    • strong causal effect of cognitive inflexibility reducing depression and anxiety and modified by education level (low education). The less flexibility, the larger improvement (Jacobsen et al. 2023).

  • conceptual shift in considering the modification in serotonin levels from being the cause of depression to acting as a permissive factor in the onset of and the recovery from the psychopathology

    • high serotonin levels lead to increased plasticity and thus to high susceptibility to change, which may promote either an improvement or a worsening according to the quality of the environment.
  • training patients to cope with harsh conditions, for instance, through cognitive behavioral therapy,62 as it is unlikely that people can rapidly and effectively change their living milieu (Wiles et al. 2013)

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